CA1221031A - Use of a cholecalciferol derivative - Google Patents
Use of a cholecalciferol derivativeInfo
- Publication number
- CA1221031A CA1221031A CA000428169A CA428169A CA1221031A CA 1221031 A CA1221031 A CA 1221031A CA 000428169 A CA000428169 A CA 000428169A CA 428169 A CA428169 A CA 428169A CA 1221031 A CA1221031 A CA 1221031A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- treatment
- fluorinated compound
- vehicle
- osteoporosis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
Abstract
ABSTRACT
The use of 24,24-difluoro-l.alpha.,25-dihydroxycholecalci-ferol as agent for the treatment of osteoporosis or for the preventive treatment of milk fever and corresponding pharmaceutical preparations.
The use of 24,24-difluoro-l.alpha.,25-dihydroxycholecalci-ferol as agent for the treatment of osteoporosis or for the preventive treatment of milk fever and corresponding pharmaceutical preparations.
Description
~lV~
The inventlon is based on the finding of novel phy-siological properties of 24,24-difluoro la,Z5-dihydroxy-cholecalciferol, hereinafter denominated the fluorinated compound. Specifically it has been found that the fluori-nated compound is active against osteoporosis and in pre-10 venting milk fever, and can thus be utilized in the treat-ment of osteoporosis by administering to a patient suffe-ring from osteoporosis an effectlve amount of the fluori-nated compound, or can be utilized in the prevention of milk fever by administering to a preparturient female 15 ruminant an effective amount of the fluorinated compound.
Accordingly, the invention relates to the fluorinated compound as an agent for the treatment of osteoporosis or the preventive treatment of milk fever. The invention also 20 relates to the use of the fluorinated compound for the aforementioned treatments as well as to pharmaceutical compositions on the basis of the fluorinated compound for these treatments and to corresponding methods of treatment comprising the administration of the fluorinated compound.
The foregoing activities of the fluorinated compound can be demonstrated in the following tests:
a) Anti-rach~ Lenic activitv in chfi~OEks White Leghorn chicks are placed on a vitamin D-deficient diet containing 1% calcium and 0.7% phosphorous, and are housed under ultraviolet-free lighting. The test compound is dissolved in propylene glycol and administered orally 35 for 21 consecutive days to the chicks which are one to two days of age at Ihe start of treatment. Controls are treated Mé/ 22.3.83 3~
with vehicle alone. The chicks are autopsied on the day after the last treatment day and the tibia ash weights are determined. Nine to ten chicks are used for each treatment group and for the control group. The mean tibia ash weights expressed in mg are given in Table I. The results show that the fluorinated compound possess potent anti-rachito-genic activity.
Table I
~ose (ng/chick/day) Mean tibla ash weight (mq) 0 120.7+5.9 1 111.7+5.8 3 151.5+4.7 227.1+8.2 244.8+7.4 20 b) Intestinal calcium absorPtion in chicks White Leghorn chicks are placed on a vitamin D-defi-cient diet and are housed under ultraviolet-free lighting for 21 days. A single oral dose of test compound dissolved 25 in propylene glycol is administered. At various times after dosing, 2 ~Ci of 45~a (chloride) are given orally and serum radioactivity is measured 45 minutes after admini-stration of the isotope. Vehicle-treated controls are included at each time period. Ten or eleven chicks are used 30 in each treatment and control group. The results given in Table II for la,25-dihydroxycholecalciferol (compound A) and for the fluorinated compound (B), show that the latter has potent intestinal calcium absorption activity of long duration (96 hours after a single oral 100 nanogram dose) 35 and consequently possesses utility in the prevention of milk fever in preparturient female ruminants.
Table II
Treatment Time (hours) Number o Serum Ca chicks(cp~/0.2 ml) Vehicle 0.2 ml 24 11 992 + 81 Compound A 100 ng 11 1800 + 181 Compound B 100 ng 11 2064 + 170 10 Vehicle 0.2 ml 48 11 769 + 90 Compound A 10~ ng 11 1006 + 133 Compound B 100 ng 11 1539 + 99 Vehicle 0.2 ml 72 10 647 + 69 15 Compound A 200 ng 11 710 + 62 Compound ~ 100 ng 11 1164 + 90 Vehicle 0.2 ml 96 10 586 + 70 Compound B 100 ng 10 998 + 61 c) Prevention of EHDP-induced mineralization block in rats Charles River male rats are treated for 10 consecuti~e days ~ith the disodium salt of ethane-1-hydroxy~ diphos-25 phonate (EHDP). This compound is given subcutaneously oneach treatment day at a dose of 2 mg/0.2 ml/rat in distilled water. The fluorinated compound is administered orally dissolved in propylene glycol on each treatment day. The rats are autopsied on the day after the last treatment day 30 and the tibias are processed by silver impregnation of the bone salts. The epiphyseal plate widths are measured with a microscope. Activity i5 based upon dose-dependent narro-wing of the widened epiphyseal plate induced by EHDP. Ten rats are used in each treatment group. Positive (EHDP alone) 35 and negative (vehicles alone) control groupsof ten rats each are included in each experiment. The results given in Table III show that the fluorinated compound calcified the tibial epiphyseal plate in EHDP-blocked rats.
3~
Table III
Dose Mean tikial epiphyseal plate width (ng/rat/day) (micron) 0 1182 + 51 1 839 + 18 3 674 + 18 540 + 16 1030 412 + 9 Vehicle controls (no EHDP) 440 + 2 The fluorinated compound can be administered in 15 dosages that are in the range of about 50-200, preferably 100 nanograms per day for the treatment of osteoporosis.
It can be administered orally, subcutaneously, intramus-cularly, intravenous~y or intraperitoneally, for instance as tablets, capsules or elixirs for oral administration, 20 or in sterile solutions or suspensions for parenteral administratiQn. About 50-200 nanograms of the fluorinated compound is compounded with a pharmaceutic~lly acceptable vehicle, carrier, excipient, binder, preservative, stabili-zer and/or flavor in a unit dosage form. Illustrative of 25 the adjuvants which may be incorporated into capsules are a binder, such as corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating, such as corn or potato starch or algenic acid; a lubricant, such as magnesium stearate; a sweetening agent, such as sucrose;
30 a flavoring agent, such as peppermint. other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, 35 methyl and propyl parabens as preservatives, a dye and a flavoring, such as orange flavor. Sterile compositions for injectlon can be formulated according to conventional pharmaceutical practice by dissolving or suspending the 3~1 fluorina~ed compound in a vehicle, such as water for lnjec-tion, a naturally-occurring vegetable oil, ~uch as sesame oil, or a synthetic fatty vehicle, such as ethyl oleate.
Buffers, preservatives and antioxidants can also be incor-porated.
The fluorinated compound can be administered indosages in the range of about 30-500 micrograms per day for the prevention of milk fever in pregnant ruminant ani-10 mals, especially in pregnant female bovines, preferablyabout one to four days prior to parturation. The fluorinated compound can be formulated for oral administration by in-corporation of 30-500 micrograms into fatty acid pellets.
Sterile compositions for injection and/or topical admini-15 stration can be formulated according to conventionalpractice by dissolving or suspending the fluorinated com-pound in a vehicle, such as a 5-10% ethanol-water mixture;
a naturally-occurring ve~etable oil, such as sesame oil;
or a synthetic fatty vehicle, such as ethyl oleate. For
The inventlon is based on the finding of novel phy-siological properties of 24,24-difluoro la,Z5-dihydroxy-cholecalciferol, hereinafter denominated the fluorinated compound. Specifically it has been found that the fluori-nated compound is active against osteoporosis and in pre-10 venting milk fever, and can thus be utilized in the treat-ment of osteoporosis by administering to a patient suffe-ring from osteoporosis an effectlve amount of the fluori-nated compound, or can be utilized in the prevention of milk fever by administering to a preparturient female 15 ruminant an effective amount of the fluorinated compound.
Accordingly, the invention relates to the fluorinated compound as an agent for the treatment of osteoporosis or the preventive treatment of milk fever. The invention also 20 relates to the use of the fluorinated compound for the aforementioned treatments as well as to pharmaceutical compositions on the basis of the fluorinated compound for these treatments and to corresponding methods of treatment comprising the administration of the fluorinated compound.
The foregoing activities of the fluorinated compound can be demonstrated in the following tests:
a) Anti-rach~ Lenic activitv in chfi~OEks White Leghorn chicks are placed on a vitamin D-deficient diet containing 1% calcium and 0.7% phosphorous, and are housed under ultraviolet-free lighting. The test compound is dissolved in propylene glycol and administered orally 35 for 21 consecutive days to the chicks which are one to two days of age at Ihe start of treatment. Controls are treated Mé/ 22.3.83 3~
with vehicle alone. The chicks are autopsied on the day after the last treatment day and the tibia ash weights are determined. Nine to ten chicks are used for each treatment group and for the control group. The mean tibia ash weights expressed in mg are given in Table I. The results show that the fluorinated compound possess potent anti-rachito-genic activity.
Table I
~ose (ng/chick/day) Mean tibla ash weight (mq) 0 120.7+5.9 1 111.7+5.8 3 151.5+4.7 227.1+8.2 244.8+7.4 20 b) Intestinal calcium absorPtion in chicks White Leghorn chicks are placed on a vitamin D-defi-cient diet and are housed under ultraviolet-free lighting for 21 days. A single oral dose of test compound dissolved 25 in propylene glycol is administered. At various times after dosing, 2 ~Ci of 45~a (chloride) are given orally and serum radioactivity is measured 45 minutes after admini-stration of the isotope. Vehicle-treated controls are included at each time period. Ten or eleven chicks are used 30 in each treatment and control group. The results given in Table II for la,25-dihydroxycholecalciferol (compound A) and for the fluorinated compound (B), show that the latter has potent intestinal calcium absorption activity of long duration (96 hours after a single oral 100 nanogram dose) 35 and consequently possesses utility in the prevention of milk fever in preparturient female ruminants.
Table II
Treatment Time (hours) Number o Serum Ca chicks(cp~/0.2 ml) Vehicle 0.2 ml 24 11 992 + 81 Compound A 100 ng 11 1800 + 181 Compound B 100 ng 11 2064 + 170 10 Vehicle 0.2 ml 48 11 769 + 90 Compound A 10~ ng 11 1006 + 133 Compound B 100 ng 11 1539 + 99 Vehicle 0.2 ml 72 10 647 + 69 15 Compound A 200 ng 11 710 + 62 Compound ~ 100 ng 11 1164 + 90 Vehicle 0.2 ml 96 10 586 + 70 Compound B 100 ng 10 998 + 61 c) Prevention of EHDP-induced mineralization block in rats Charles River male rats are treated for 10 consecuti~e days ~ith the disodium salt of ethane-1-hydroxy~ diphos-25 phonate (EHDP). This compound is given subcutaneously oneach treatment day at a dose of 2 mg/0.2 ml/rat in distilled water. The fluorinated compound is administered orally dissolved in propylene glycol on each treatment day. The rats are autopsied on the day after the last treatment day 30 and the tibias are processed by silver impregnation of the bone salts. The epiphyseal plate widths are measured with a microscope. Activity i5 based upon dose-dependent narro-wing of the widened epiphyseal plate induced by EHDP. Ten rats are used in each treatment group. Positive (EHDP alone) 35 and negative (vehicles alone) control groupsof ten rats each are included in each experiment. The results given in Table III show that the fluorinated compound calcified the tibial epiphyseal plate in EHDP-blocked rats.
3~
Table III
Dose Mean tikial epiphyseal plate width (ng/rat/day) (micron) 0 1182 + 51 1 839 + 18 3 674 + 18 540 + 16 1030 412 + 9 Vehicle controls (no EHDP) 440 + 2 The fluorinated compound can be administered in 15 dosages that are in the range of about 50-200, preferably 100 nanograms per day for the treatment of osteoporosis.
It can be administered orally, subcutaneously, intramus-cularly, intravenous~y or intraperitoneally, for instance as tablets, capsules or elixirs for oral administration, 20 or in sterile solutions or suspensions for parenteral administratiQn. About 50-200 nanograms of the fluorinated compound is compounded with a pharmaceutic~lly acceptable vehicle, carrier, excipient, binder, preservative, stabili-zer and/or flavor in a unit dosage form. Illustrative of 25 the adjuvants which may be incorporated into capsules are a binder, such as corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating, such as corn or potato starch or algenic acid; a lubricant, such as magnesium stearate; a sweetening agent, such as sucrose;
30 a flavoring agent, such as peppermint. other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, 35 methyl and propyl parabens as preservatives, a dye and a flavoring, such as orange flavor. Sterile compositions for injectlon can be formulated according to conventional pharmaceutical practice by dissolving or suspending the 3~1 fluorina~ed compound in a vehicle, such as water for lnjec-tion, a naturally-occurring vegetable oil, ~uch as sesame oil, or a synthetic fatty vehicle, such as ethyl oleate.
Buffers, preservatives and antioxidants can also be incor-porated.
The fluorinated compound can be administered indosages in the range of about 30-500 micrograms per day for the prevention of milk fever in pregnant ruminant ani-10 mals, especially in pregnant female bovines, preferablyabout one to four days prior to parturation. The fluorinated compound can be formulated for oral administration by in-corporation of 30-500 micrograms into fatty acid pellets.
Sterile compositions for injection and/or topical admini-15 stration can be formulated according to conventionalpractice by dissolving or suspending the fluorinated com-pound in a vehicle, such as a 5-10% ethanol-water mixture;
a naturally-occurring ve~etable oil, such as sesame oil;
or a synthetic fatty vehicle, such as ethyl oleate. For
2~ example, a suitable formulation for intravenous injection would be 2-3 ml of a 5-10% ethanol-water solution containing 30-500, preferably 30-400 micrograms of the fluorinated compound. Exemplary of a suitable formulation for topical administration would be a vegetable oil solution or sus-25 pension containing 30-500, preferably 250-50Q micrograms of the fluorinated compound. The fluorinated compound may also be formulated for intramuscular injection by suspension of 50-500 micrograms of the fluorinated compound in a vehicle such as a 5-10% ethanol-water mixture or a 5-10% propylene 30 glycol-water mixture. Buffers, preservatives and/or anti-oxidants can be incorporated into the foregoing formula-tions as required.
3~
Example A capsule for the treatment of osteoporosls con-taining pro capsule:
1. 24,24-difluoro-la,25-dihydroxycholecalciferol 50 ng 100 ng 200 ng 2. polyethylene glycol 400 200 mg 200 mg 200 mg 3. butylated hydroxyanisole 0.1 mg 0.1 mg 0.1 mg 10 4. ascorbyl palmitate1.0 mg 1.0 mg 1.0 mg may be obtained by dissolving items 1, 3 and 4 in item 2 under an atmophere of nitrogen and encapsulating.
Example A capsule for the treatment of osteoporosls con-taining pro capsule:
1. 24,24-difluoro-la,25-dihydroxycholecalciferol 50 ng 100 ng 200 ng 2. polyethylene glycol 400 200 mg 200 mg 200 mg 3. butylated hydroxyanisole 0.1 mg 0.1 mg 0.1 mg 10 4. ascorbyl palmitate1.0 mg 1.0 mg 1.0 mg may be obtained by dissolving items 1, 3 and 4 in item 2 under an atmophere of nitrogen and encapsulating.
Claims (6)
1. Pharmaceutical compositions containing 24,24-difluoro-1.alpha.,25-dihydroxycholecalciferol, in combination with a pharmaceutically acceptable inert carrier material, for the treatment of osteoporosis or for the preventive treatment of milk fever.
2. Pharmaceutical compositions containing 24,24-difluoro-1.alpha.,25-dihydroxycholecalciferol, in combination with a pharmaceutically acceptable inert carrier material, for the treatment of osteoporosis.
3. A composition as in claim 2 wherein the amount of the active ingredient is from about 50 to 200 nanograms.
4. A pharmaceutical composition as in claim 2 wherein the amount of the active ingredient is about 100 nanograms.
5. A pharmaceutical composition containing 24,24-difluoro-1.alpha.,25-dihydroxycholecalciferol, in combination with a pharmaceutically acceptable inert carrier material, for the preventive treatment of milk fever.
6. A pharmaceutical composition as in claim 5 wherein the active ingredient is from about 30 to 500 micrograms.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US379,384 | 1982-05-17 | ||
| US379,385 | 1982-05-17 | ||
| US06/379,384 US4397847A (en) | 1982-05-17 | 1982-05-17 | Method of treatment |
| US06/379,385 US4599330A (en) | 1982-05-17 | 1982-05-17 | Method of treating milk fever |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1221031A true CA1221031A (en) | 1987-04-28 |
Family
ID=27008599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000428169A Expired CA1221031A (en) | 1982-05-17 | 1983-05-13 | Use of a cholecalciferol derivative |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0094644B1 (en) |
| AU (1) | AU563733B2 (en) |
| CA (1) | CA1221031A (en) |
| DE (2) | DE3364904D1 (en) |
| IE (1) | IE55230B1 (en) |
| IL (1) | IL68695A (en) |
| IT (1) | IT1171672B (en) |
| NZ (1) | NZ204223A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4428946A (en) * | 1982-07-26 | 1984-01-31 | Wisconsin Alumni Research Foundation | Method of preventing milk fever in dairy cattle |
| CA1272953A (en) | 1984-10-08 | 1990-08-21 | Yuji Makino | Pharmaceutical composition for external use containing active-type vitamin d.sub.3 |
| JP2856444B2 (en) * | 1989-07-28 | 1999-02-10 | 呉羽化学工業株式会社 | Vitamin D lower 3 metabolite preparation |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3646203A (en) * | 1969-04-30 | 1972-02-29 | Wisconsin Alumni Res Found | Method of treating milk fever in dairy cattle with 25-hydroxycholecalciferol |
| US3879548A (en) * | 1974-01-21 | 1975-04-22 | Wisconsin Alumni Res Found | Method of treating milk fever in dairy cattle with 1-alpha-hydroxycholecalciferol |
| US4110446A (en) * | 1977-07-14 | 1978-08-29 | Wisconsin Alumni Research Foundation | Method of treating milk fever in dairy cattle with 1,25-dihydroxycholecalciferol |
| US4284577A (en) * | 1979-02-16 | 1981-08-18 | Sachiko Yamada | Novel vitamin D3 derivative and process for preparing the same |
| US4201881A (en) * | 1979-03-28 | 1980-05-06 | Wisconsin Alumni Research Foundation | 24,24-Difluoro-1α,25-dihydroxycholecalciferol |
-
1983
- 1983-05-13 EP EP83104746A patent/EP0094644B1/en not_active Expired
- 1983-05-13 DE DE8383104746T patent/DE3364904D1/en not_active Expired
- 1983-05-13 DE DE19833317562 patent/DE3317562A1/en not_active Withdrawn
- 1983-05-13 CA CA000428169A patent/CA1221031A/en not_active Expired
- 1983-05-13 IL IL68695A patent/IL68695A/en unknown
- 1983-05-13 NZ NZ204223A patent/NZ204223A/en unknown
- 1983-05-16 IE IE1131/83A patent/IE55230B1/en unknown
- 1983-05-16 AU AU14562/83A patent/AU563733B2/en not_active Ceased
- 1983-05-17 IT IT21128/83A patent/IT1171672B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IE55230B1 (en) | 1990-07-04 |
| EP0094644A1 (en) | 1983-11-23 |
| IE831131L (en) | 1983-11-17 |
| IT1171672B (en) | 1987-06-10 |
| AU563733B2 (en) | 1987-07-23 |
| AU1456283A (en) | 1983-11-24 |
| DE3317562A1 (en) | 1983-11-17 |
| DE3364904D1 (en) | 1986-09-04 |
| IL68695A (en) | 1986-01-31 |
| NZ204223A (en) | 1986-11-12 |
| IL68695A0 (en) | 1983-09-30 |
| EP0094644B1 (en) | 1986-07-30 |
| IT8321128A0 (en) | 1983-05-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4282217A (en) | Pharmaceutical compositions containing a corticosteroid substance | |
| EP0659402A2 (en) | Formulations containing carotenoids and procarotenoids combined with polyphenols in the prevention of the damages due to an abnormal production of free radicals | |
| US20040109905A1 (en) | Method and composition of anthocyanin-rich berry extracts that prevents or inhibits angiogenesis and helicobacter pylori and acts as a powerful antioxidant that provides various health benefits | |
| IL76777A (en) | Inositoltriphosphates,their preparation and pharmaceutical compositions containing them | |
| RU93051780A (en) | CONTROLLED RELEASE COMPOSITIONS CONTAINING OXYCODONE, METHOD FOR REDUCING DAILY DOSES OF PRODUCTS CONTAINING OXYCODON | |
| DE3907649C2 (en) | Medicines suitable for the control of viruses and for immunostimulation | |
| EP0629400B1 (en) | Idebenone compositions for treating Alzheimer's disease | |
| Kornberg et al. | Granulocytopenia and anemia in rats fed diets of low casein content | |
| FR2244468A1 (en) | Anticarcinogenic food supplements - contg antioxidants and S-contg amino acids | |
| CA1221031A (en) | Use of a cholecalciferol derivative | |
| CA2340227C (en) | Method and pharmaceutical composition for reducing serum homocysteine concentration | |
| GB2098066A (en) | Vitamin d3 derivatives for preventing parturient paresis in dairy cattle | |
| US3852453A (en) | Method of enhancing vincamine compositions | |
| US4578400A (en) | Therapeutic composition and method for treatment of cardiovascular diseases | |
| EP0127297B1 (en) | Vitamin composition with enhanced bioavailability and method of administering same | |
| CA1206882A (en) | Use of cholecalciferol derivatives | |
| US6358997B1 (en) | Tocopherol and tocotrienol compositions | |
| Likins et al. | Calcification in lysine deficiency | |
| CA2346647C (en) | Treatment of dyspepsia | |
| McCarty et al. | Rationales for micronutrient supplementation in diabetes | |
| JPH0563452B2 (en) | ||
| Koletsky et al. | Effect of antibiotics on mortality from internal radiation. | |
| IE56895B1 (en) | Anticoccidial compositions | |
| US3067242A (en) | Di-(n, n-dimethyloctadecylamine) pamoate | |
| US3360434A (en) | Method for reducing blood pressure with phenylalanine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |